Thomas Ondrey, The Plain DealerJorge Viglienghi, left, takes his medicine along with crackers and some laughs during a checkup last week with Dr. Michael Vogelbaum, right, of the Cleveland Clinic. Viglienghi is the first patient at the Clinic -- and only the sixth in the country -- to take part in the Tocagen trial being conducted locally by Vogelbaum, a neurosurgeon.

CLEVELAND, Ohio -- All cancerous brain tumors are not equal.

There are more than 120 types. But glioblastoma multiforme, one of the most devastating, has long frustrated neurologists and neuro-oncologists.

The best five-year survival rate -- 20 percent -- occurs in people ages 19 and under. The older the patient, the worse the prognosis. People over age 44 diagnosed with a glioblastoma face a survival rate below 6 percent.

But in recent years, researchers have begun to offer patients more experimental therapies that have made many in the field of oncology hopeful that they can provide those patients with better survival rates.

By the numbers

In 2011, about 22,340 cases of malignant tumors of the brain or spinal cord will be diagnosed in the United States, according to the American Cancer Society. About 13,110 people will die from malignant brain tumors this year.

The Cleveland Clinic is one of only three centers in the United States with patients in a new clinical trial testing a retroviral gene therapy developed by the California-based biopharmaceuticalcompany Tocagen. That therapy, for use in patients with recurrent high-grade glioblastomas, is followed up a few weeks later with an oral drug.

Dr. Andrew Sloan, director of the Brain Tumor and Neuro-Oncology Center at University Hospitals Case Medical Center, is overseeing three separate clinical trials testing two different therapeutic vaccines to treat glioblastomas.

"We've been slowly chipping away at glioblastomas over the last couple decades," said Dr. Gene Barnett, director of the Clinic's Burkhardt Brain Tumor Center.

"With gradual improvements, today patients with the diagnosis are better off and live longer than they did 20 years ago, overall. But that said, there's still lots of room for improvement."

Several factors compound the difficulty in treating glioblastomas. Because they are situated in the brain, surgical removal is sometimes limited.

Rather than growing in a lump, the tumors spread out among normal brain tissue -- which means that even when 99.99 percent of the malignant cells are removed surgically, there will still be active tumor cells that a surgeon just can't capture.

Those remaining cells are often very resistant to chemotherapy and radiation.

The advent of new trials offers much-needed hope, said Barnett, but the fact remains that "the glioblastoma highway is littered with thousands and thousands of trials over the last couple of decades that just haven't worked out."

Vaccine therapyshows promise

In June, at the annual meeting of the American Society of Clinical Oncology, Sloan presented what he called "extremely favorable" results of a Phase 2 clinical trial of HSppC-96, a vaccine that isolates something called heat shock protein, which alerts the immune system to attack, from a patient's tumor.

Clinical trials for treating glioblastoma multiforme

At University Hospitals Case Medical Center, several Phase 2 clinical trials testing therapeutic vaccines using a patient's own tumor are under way or will soon open.

In June, a study of the vaccine DCVax-L, in development by Maryland-based Northwest Biotherapeutics for the past 10 years, resumed at UH after a two-year hiatus caused by the company's funding issues.

Before the year is out, UH is expected to enroll patients in a trial of the same vaccine that Leslie Robertson started taking in 2009. Instead of enrolling patients like Robertson, who had a recurrent cancerous brain tumor, the trial will be for patients with newly diagnosed brain cancer.

Over the past few months, several patients have taken part in a trial designed to see if the drug 5-Aminolevulinic Acid, or 5-ALA, is effective in helping surgeons spot and remove tumor cells. Patients take the drug orally before surgery. The drug makes brain tumor cells glow pink when they are illuminated with a special blue light on the operating microscope.

In the spring, the Cleveland Clinic began enrolling newly diagnosed patients who have completed radiation and chemotherapy in a Phase 3 clinical trial for a therapy developed by the company Novocure, whose U.S. operations are based in New Hampshire. The company created a portable device — approved in April by the Food and Drug Administration — that sits on a patient's head like a shower cap. The electrodes on the device deliver a relatively low frequency of electromagnetic waves, essentially tuned to the frequency that is involved in internal components of a cell that allow it to divide.

The Clinic and UH are two of 17 sites across the country taking part in a new vaccine clinical trial developed by the Los Angeles-based company ImmunoCellular Therapeutics that involves identifying the presence or absence of peptides on a tumor sample. A process called leukapheresis harvests a patient's immune cells, "pulsed" with a synthetic version of whichever peptides are present in the patient's tumor, then injected back into the patient. If successful, the cells will trigger an immune response that can attack the cancer.

That protein is reinjected into the skin with an agent added to a drug to increase its effect, in the hopes that the custom-made vaccine can prevent a recurrence of the tumor.

Leslie Robertson, one of 10 UH patients who were enrolled in that trial, is living proof of those favorable results. Originally diagnosed with Stage 4 glioblastoma in December 2008, he traveled from his home in Maine to join the trial in March 2009, one month after surgery for a recurrence.

Robertson, 54, received his last vaccine injection in May 2010. Since then he has had no other treatment. A follow-up CT scan taken in mid-October showed no signs of a recurrence.

"I'm surprised that I'm still here," he said.

"We didn't know how much time the vaccine would buy us," said Robertson's significant other, Linda Smith. "For it to be this long, it is amazing."

Twenty years ago, the idea of creating a therapeutic vaccine for brain tumors was a hot topic.

As the years went on, vaccine research interest has come and gone and come again.

Sloan said he has always been intrigued by the riddle of brain cancer. "And I was interested in the potential for vaccines."

More than a decade ago, the Clinic ran a pioneering therapeutic vaccine trial for glioblastoma.

The trial was initially successful in shrinking tumors, but they eventually recurred months later. And the number of recruited patients who actually received treatment was small.

"Probably only 5 percent enrolled ever got treated because it was such a complicated technique," Barnett said. "So it wasn't practical as a routine treatment.

"We found that, indeed, there were some patients who did respond," Barnett said. "But the field of immunotherapy has been plagued, I think, by the fact that almost all our patients are on high doses of steroids at one point or another [as part of] their treatment." That, in turn, tears down the immune system of a sizable number of patients..

The fact that certain patients do havethat reaction shows that therapeutic vaccines have not been "home runs," despite their earlier promise, Barnett said.

"Actually, I think that probably the niche for immunotherapy down the road will be in patients with low-grade tumors," Barnett said. But because those low-grade tumors are slower growing and tend not to mutate over time, "You may have a successful vaccine against a particular tumor but then it mutates into something else. And the vaccine doesn't cover it."

That hasn't stopped physician researchers like Sloan at UH from continuing to move forward with vaccine trials. One of the main attractions to vaccines is that, unlike chemotherapy -- which can damage bone marrow over time -- or radiation, they have almost no toxicity.

Noncancer vaccines, such as those for smallpox and polio, have positive long-lasting effects.

"There is no reason to believe that the same wouldn't be true [for cancer] if they worked," Sloan said. "We have to figure out how they work."

Retrovirus gene therapytested at the Clinic

For the Clinic, however, the focus has turned to other novel therapies such as Tocagen. In September, Jorge Viglienghi of Willoughby became the first patient at the Clinic -- and only the sixth patient in the country -- enrolled in the Phase 2 clinical trial.

"The virus enters the cell and only [moves to] cells that are replicating or reproducing in the brain," said Barnett, director of the Clinic's brain tumor center, who likens the therapy to a Trojan horse. "It goes on to affect other tumor cells. Ideally the entire tumor isinfected. And then, you release a certain drug into body that causes any cell it has affected to die. The cell welcomes the virus in -- only for it to turn against them."

Viglienghi, 61, was diagnosed with a glioblastoma in March 2010. Several months ago, a follow-up MRI showed evidence that the tumor was growing back, despite treatment with surgery, radiation and chemotherapy. Because the tumor was still relatively small, Viglienghi's physicians suggested that he take part in the Tocagen trial.

On Sept. 7, neurosurgeon Dr. Michael Vogelbaum biopsied a small part of the tumor, then injected the retrovirus right onto the active tumor cells. A few weeks later, Viglienghi started taking the oral medication 5-fluorocytosine, or 5FC, which starts out benign but converts into a potent chemotherapy once it reaches the tumor cells.

Viglienghi must take four pills every four hours for six days straight, a regimen that he repeats every month indefinitely, as long as his tumor doesn't grow any larger. He wasn't initially thrilled with the idea of having to take so much medication, but had a change of heart.

"I want to stay alive," he said last week. "It could be better, but it's not that difficult."

Even with promising clinical trials being offered to more patients, no one really knows what the big treatment breakthrough for glioblastomas will be.

"I suspect that if a breakthrough is going to happen, it's going to be using some nontraditional therapy," Barnett said. "I think it's going to be something out of the box. Those, I think, really have the greatest promise to be a game changer compared to things that have been tried over and over and over and over for the last two, three decades with only marginal benefits."

Clues to Cancer: Patients, doctors on road to discovery

For 10 months, Plain Dealer reporter Angela Townsend and photographer Lynn Ischay followed 9 patients through their journey as study participants in Phase 1 trials at University Hospitals. We tell their stories here.

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